US20200345870A1 - Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor - Google Patents
Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor Download PDFInfo
- Publication number
- US20200345870A1 US20200345870A1 US16/929,803 US202016929803A US2020345870A1 US 20200345870 A1 US20200345870 A1 US 20200345870A1 US 202016929803 A US202016929803 A US 202016929803A US 2020345870 A1 US2020345870 A1 US 2020345870A1
- Authority
- US
- United States
- Prior art keywords
- fluorine
- radiotracer
- precursor
- labeled
- reaction solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000700 radioactive tracer Substances 0.000 title claims abstract description 100
- 102000009206 Translocator proteins Human genes 0.000 title claims abstract description 72
- 108050000091 Translocator proteins Proteins 0.000 title claims abstract description 72
- 230000002018 overexpression Effects 0.000 title claims abstract description 39
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 29
- 238000002600 positron emission tomography Methods 0.000 title claims description 35
- 239000003446 ligand Substances 0.000 title claims description 24
- 238000002428 photodynamic therapy Methods 0.000 title claims description 16
- 238000001356 surgical procedure Methods 0.000 title claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 7
- 201000010099 disease Diseases 0.000 title description 4
- 230000018883 protein targeting Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- 239000002243 precursor Substances 0.000 claims abstract description 104
- -1 4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl Chemical group 0.000 claims abstract description 66
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 53
- 229910052796 boron Inorganic materials 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims description 74
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 31
- 230000008685 targeting Effects 0.000 claims description 31
- 239000002202 Polyethylene glycol Substances 0.000 claims description 30
- 229920001223 polyethylene glycol Polymers 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000007850 fluorescent dye Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 125000000524 functional group Chemical group 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- 229910052727 yttrium Inorganic materials 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 11
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 10
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 9
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 8
- DOUMBTAZXRQKGF-UHFFFAOYSA-L copper pyridine trifluoromethanesulfonate Chemical compound [Cu++].c1ccncc1.c1ccncc1.c1ccncc1.c1ccncc1.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DOUMBTAZXRQKGF-UHFFFAOYSA-L 0.000 claims description 8
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 8
- 230000005251 gamma ray Effects 0.000 claims description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 8
- ADEYHRTVCVJFAU-UHFFFAOYSA-N iodobenzene;4-methylbenzenesulfonic acid Chemical compound IC1=CC=CC=C1.CC1=CC=C(S(O)(=O)=O)C=C1 ADEYHRTVCVJFAU-UHFFFAOYSA-N 0.000 claims description 5
- RRTIHICTXUYTFO-UHFFFAOYSA-N 1-iodo-3-methoxybenzene 4-methylbenzenesulfonic acid Chemical compound COC1=CC=CC(I)=C1.CC1=CC=C(S(O)(=O)=O)C=C1 RRTIHICTXUYTFO-UHFFFAOYSA-N 0.000 claims description 4
- MIHYXRVEUXZYGW-UHFFFAOYSA-N 1-iodo-3-methoxybenzene hydrobromide Chemical compound Br.COC1=CC=CC(I)=C1 MIHYXRVEUXZYGW-UHFFFAOYSA-N 0.000 claims description 4
- MZQBZKZAIBDLPJ-UHFFFAOYSA-N 1-iodo-3-methoxybenzene hydroiodide Chemical compound I.COc1cccc(I)c1 MZQBZKZAIBDLPJ-UHFFFAOYSA-N 0.000 claims description 4
- ZXAYYOOVMSZWCZ-UHFFFAOYSA-N 1-iodo-3-methoxybenzene trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F.COC1=CC=CC(I)=C1 ZXAYYOOVMSZWCZ-UHFFFAOYSA-N 0.000 claims description 4
- PRKIOFRSDJFNAU-UHFFFAOYSA-N 1-iodo-4-methoxybenzene 4-methylbenzenesulfonic acid Chemical compound COC1=CC=C(I)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1 PRKIOFRSDJFNAU-UHFFFAOYSA-N 0.000 claims description 4
- LQXCRTMNFBGGST-UHFFFAOYSA-N 1-iodo-4-methoxybenzene trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F.COC1=CC=C(I)C=C1 LQXCRTMNFBGGST-UHFFFAOYSA-N 0.000 claims description 4
- JXHPIDWQJQMCLH-UHFFFAOYSA-N 2-iodo-1,3,5-trimethylbenzene 4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(C=C1)S(=O)(=O)O.CC1=CC(=C(C(=C1)C)I)C JXHPIDWQJQMCLH-UHFFFAOYSA-N 0.000 claims description 4
- GFZBJUSMPHHOEA-UHFFFAOYSA-N 2-iodothiophene 4-methylbenzenesulfonic acid Chemical compound IC1=CC=CS1.CC1=CC=C(S(O)(=O)=O)C=C1 GFZBJUSMPHHOEA-UHFFFAOYSA-N 0.000 claims description 4
- ZTXLCSNXWJGUGR-UHFFFAOYSA-N 2-iodothiophene trifluoromethanesulfonic acid Chemical compound IC1=CC=CS1.OS(=O)(=O)C(F)(F)F ZTXLCSNXWJGUGR-UHFFFAOYSA-N 0.000 claims description 4
- VMZDYSYZFKKDFM-UHFFFAOYSA-N 3-iodothiophene 4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(C=C1)S(=O)(=O)O.C1=CSC=C1I VMZDYSYZFKKDFM-UHFFFAOYSA-N 0.000 claims description 4
- SPZRHFITEWOOAG-UHFFFAOYSA-N 3-iodothiophene hydrobromide Chemical compound Br.Ic1ccsc1 SPZRHFITEWOOAG-UHFFFAOYSA-N 0.000 claims description 4
- ISTMWFGIXLEPFJ-UHFFFAOYSA-N 3-iodothiophene trifluoromethanesulfonic acid Chemical compound Ic1ccsc1.OS(=O)(=O)C(F)(F)F ISTMWFGIXLEPFJ-UHFFFAOYSA-N 0.000 claims description 4
- JVJZJFLJQTZBFN-UHFFFAOYSA-N Br.ICC1=CC=CC=C1 Chemical compound Br.ICC1=CC=CC=C1 JVJZJFLJQTZBFN-UHFFFAOYSA-N 0.000 claims description 4
- IEEIPGUFMXZMGQ-UHFFFAOYSA-N CC(C=C1C)=CC(C)=C1I.Br Chemical compound CC(C=C1C)=CC(C)=C1I.Br IEEIPGUFMXZMGQ-UHFFFAOYSA-N 0.000 claims description 4
- FMNUPLQTSFWLSL-UHFFFAOYSA-N CC(C=C1C)=CC(C)=C1I.I Chemical compound CC(C=C1C)=CC(C)=C1I.I FMNUPLQTSFWLSL-UHFFFAOYSA-N 0.000 claims description 4
- WZTYPAMFWFQZBZ-UHFFFAOYSA-N CC(C=C1C)=CC(C)=C1I.OS(C(F)(F)F)(=O)=O Chemical compound CC(C=C1C)=CC(C)=C1I.OS(C(F)(F)F)(=O)=O WZTYPAMFWFQZBZ-UHFFFAOYSA-N 0.000 claims description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 4
- OHQUIXJYUQJJTA-UHFFFAOYSA-N FC(S(=O)(=O)O)(F)F.C(C1=CC=CC=C1)I Chemical compound FC(S(=O)(=O)O)(F)F.C(C1=CC=CC=C1)I OHQUIXJYUQJJTA-UHFFFAOYSA-N 0.000 claims description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 4
- MYUUKMPJICFHBF-UHFFFAOYSA-N I.COc1ccc(I)cc1 Chemical compound I.COc1ccc(I)cc1 MYUUKMPJICFHBF-UHFFFAOYSA-N 0.000 claims description 4
- NGXNYYHABKPOQV-UHFFFAOYSA-N IC1=CC=CS1.I Chemical compound IC1=CC=CS1.I NGXNYYHABKPOQV-UHFFFAOYSA-N 0.000 claims description 4
- SLGATDUYWCZZJW-UHFFFAOYSA-N IC1=CSC=C1.I Chemical compound IC1=CSC=C1.I SLGATDUYWCZZJW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- XORMCLNJBIOTIE-UHFFFAOYSA-N iodobenzene hydrobromide Chemical compound Br.Ic1ccccc1 XORMCLNJBIOTIE-UHFFFAOYSA-N 0.000 claims description 4
- VVCSAFKCSAAZMU-UHFFFAOYSA-N iodobenzene hydroiodide Chemical compound C1=CC=C(C=C1)I.I VVCSAFKCSAAZMU-UHFFFAOYSA-N 0.000 claims description 4
- BAFRDXKXMYNVCT-UHFFFAOYSA-N iodobenzene;trifluoromethanesulfonic acid Chemical compound IC1=CC=CC=C1.OS(=O)(=O)C(F)(F)F BAFRDXKXMYNVCT-UHFFFAOYSA-N 0.000 claims description 4
- GRAKFRLAJBIFQS-UHFFFAOYSA-N iodomethylbenzene hydroiodide Chemical compound I.ICC1=CC=CC=C1 GRAKFRLAJBIFQS-UHFFFAOYSA-N 0.000 claims description 4
- 238000001179 sorption measurement Methods 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 150000002540 isothiocyanates Chemical class 0.000 claims description 3
- 125000000963 oxybis(methylene) group Chemical group [H]C([H])(*)OC([H])([H])* 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 claims 24
- 206010028980 Neoplasm Diseases 0.000 abstract description 23
- 230000003959 neuroinflammation Effects 0.000 abstract description 15
- 208000036110 Neuroinflammatory disease Diseases 0.000 abstract description 14
- 125000003118 aryl group Chemical group 0.000 abstract description 10
- 210000004556 brain Anatomy 0.000 abstract description 10
- 208000006011 Stroke Diseases 0.000 abstract description 8
- 238000003384 imaging method Methods 0.000 abstract description 6
- 208000003174 Brain Neoplasms Diseases 0.000 abstract description 5
- 150000001450 anions Chemical class 0.000 abstract description 5
- OKTJSMMVPCPJKN-BJUDXGSMSA-N carbon-11 Chemical compound [11C] OKTJSMMVPCPJKN-BJUDXGSMSA-N 0.000 abstract description 5
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 abstract description 5
- 208000014644 Brain disease Diseases 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- PUZPDOWCWNUUKD-ULWFUOSBSA-M sodium;fluorine-18(1-) Chemical compound [18F-].[Na+] PUZPDOWCWNUUKD-ULWFUOSBSA-M 0.000 abstract 6
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 97
- 239000000243 solution Substances 0.000 description 63
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 238000012879 PET imaging Methods 0.000 description 15
- 230000027455 binding Effects 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 229940016681 dipropylacetamide Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000002372 labelling Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 0 *C.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound *C.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 0.000 description 7
- PQGKWCKYFBPFOB-UHFFFAOYSA-N 2-[6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide Chemical compound ClC=1C=C(C=2N(C=1)C(=C(N=2)C1=CC=C(C=C1)F)CC(=O)N(CCC)CCC)Cl PQGKWCKYFBPFOB-UHFFFAOYSA-N 0.000 description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- XJHCXCQVJFPJIK-UHFFFAOYSA-M cesium fluoride Substances [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 7
- OMOMUFTZPTXCHP-UHFFFAOYSA-N valpromide Chemical compound CCCC(C(N)=O)CCC OMOMUFTZPTXCHP-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 6
- 229920006008 lipopolysaccharide Polymers 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000002025 microglial effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000011552 rat model Methods 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 5
- RVXBOOYSPZAHIU-UHFFFAOYSA-N 2-[2-(4-bromophenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide Chemical compound CCCN(CCC)C(=O)Cc1c(nc2c(Cl)cc(Cl)cn12)-c1ccc(Br)cc1 RVXBOOYSPZAHIU-UHFFFAOYSA-N 0.000 description 4
- QFLNDQHHBQNSPR-UHFFFAOYSA-N 2-[6,8-dichloro-2-(4-trimethylstannylphenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide Chemical compound ClC=1C=C(C=2N(C=1)C(=C(N=2)C1=CC=C(C=C1)[Sn](C)(C)C)CC(=O)N(CCC)CCC)Cl QFLNDQHHBQNSPR-UHFFFAOYSA-N 0.000 description 4
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 4
- QYXOMZGYFZLBJH-HGFUGSOXSA-N CC.CC(C)B1OC(C)(C)C(C)(C)O1.CC(C)[I+]C1=CC(CO)=CC=C1.CC(C)[I+]C1=CC=C(CO)C=C1.CC(C)[I+]C1=CC=CC=C1.CC(C)[I+]C1=CC=CS1.CC(C)[I+]C1=CSC=C1.CC1=CC(C)=C([I+]C(C)C)C(C)=C1.CC1=CC=C([I+]C(C)C)C=C1.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CC.CC(C)B1OC(C)(C)C(C)(C)O1.CC(C)[I+]C1=CC(CO)=CC=C1.CC(C)[I+]C1=CC=C(CO)C=C1.CC(C)[I+]C1=CC=CC=C1.CC(C)[I+]C1=CC=CS1.CC(C)[I+]C1=CSC=C1.CC1=CC(C)=C([I+]C(C)C)C(C)=C1.CC1=CC=C([I+]C(C)C)C=C1.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 QYXOMZGYFZLBJH-HGFUGSOXSA-N 0.000 description 4
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 4
- BBNQQADTFFCFGB-UHFFFAOYSA-N purpurin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC(O)=C3C(=O)C2=C1 BBNQQADTFFCFGB-UHFFFAOYSA-N 0.000 description 4
- 239000012925 reference material Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 3
- HMSMOZAIMDNRBW-UHFFFAOYSA-N 100572-96-1 Chemical compound C1=CC2=NC1=CC=C(N1)C=CC1=C(N1)C=CC1=CC=C1C=CC2=N1 HMSMOZAIMDNRBW-UHFFFAOYSA-N 0.000 description 3
- VUZNLSBZRVZGIK-UHFFFAOYSA-N 2,2,6,6-Tetramethyl-1-piperidinol Chemical group CC1(C)CCCC(C)(C)N1O VUZNLSBZRVZGIK-UHFFFAOYSA-N 0.000 description 3
- PQGKWCKYFBPFOB-MIGPCILRSA-N 2-[6,8-dichloro-2-(4-(18F)fluoranylphenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide Chemical compound ClC=1C=C(C=2N(C=1)C(=C(N=2)C1=CC=C(C=C1)[18F])CC(=O)N(CCC)CCC)Cl PQGKWCKYFBPFOB-MIGPCILRSA-N 0.000 description 3
- OCWBGKZFOYMCCN-UHFFFAOYSA-N 3,5-dichloropyridin-2-amine Chemical compound NC1=NC=C(Cl)C=C1Cl OCWBGKZFOYMCCN-UHFFFAOYSA-N 0.000 description 3
- UHCCXDGYOKVIQM-IVMHHZOPSA-M C=C=NC(C)C.C=C=NC(C)C.CC(=O)C(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C(=O)ON1C(=O)CC(S(=O)(=O)O[Na])C1=O.CC(C)C(=O)ON1C(=O)CCC1=O.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCOC Chemical compound C=C=NC(C)C.C=C=NC(C)C.CC(=O)C(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C.CC(C)C(=O)ON1C(=O)CC(S(=O)(=O)O[Na])C1=O.CC(C)C(=O)ON1C(=O)CCC1=O.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCOC UHCCXDGYOKVIQM-IVMHHZOPSA-M 0.000 description 3
- UNZVHEOIJJVUCV-DSVWWHGVSA-N CC(C)NC(=O)C(C)C.CC(C)NC(=O)C(C)C.CC(C)NC(=O)NC(C)C.CC(C)NC(=O)OC(C)C.CC(C)NC(=O)OC(C)C.CC(C)NC(=S)NC(C)C.CC(C)OC(=O)C(C)C.CC(C)OC(=O)C(C)C.CC(C)OC(C)C.CC(C)SC(C)C.CC(C)SSC(C)C.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCOC Chemical compound CC(C)NC(=O)C(C)C.CC(C)NC(=O)C(C)C.CC(C)NC(=O)NC(C)C.CC(C)NC(=O)OC(C)C.CC(C)NC(=O)OC(C)C.CC(C)NC(=S)NC(C)C.CC(C)OC(=O)C(C)C.CC(C)OC(=O)C(C)C.CC(C)OC(C)C.CC(C)SC(C)C.CC(C)SSC(C)C.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCOC UNZVHEOIJJVUCV-DSVWWHGVSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 210000004004 carotid artery internal Anatomy 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 125000003827 glycol group Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 210000001259 mesencephalon Anatomy 0.000 description 3
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 3
- DCRZYADKQRHHSF-KTXUZGJCSA-N n-[(2,5-dimethoxyphenyl)methyl]-n-(5-fluoro-2-phenoxyphenyl)acetamide Chemical compound COC1=CC=C(O[11CH3])C(CN(C(C)=O)C=2C(=CC=C(F)C=2)OC=2C=CC=CC=2)=C1 DCRZYADKQRHHSF-KTXUZGJCSA-N 0.000 description 3
- RAVIZVQZGXBOQO-KTXUZGJCSA-N n-butan-2-yl-1-(2-chlorophenyl)-n-methylisoquinoline-3-carboxamide Chemical compound N=1C(C(=O)N([11CH3])C(C)CC)=CC2=CC=CC=C2C=1C1=CC=CC=C1Cl RAVIZVQZGXBOQO-KTXUZGJCSA-N 0.000 description 3
- 230000002314 neuroinflammatory effect Effects 0.000 description 3
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 description 2
- VYSOSFKAKYAENT-UHFFFAOYSA-N 3-bromo-4-(4-fluorophenyl)-4-oxo-N,N-dipropylbutanamide Chemical compound BrC(CC(=O)N(CCC)CCC)C(=O)C1=CC=C(C=C1)F VYSOSFKAKYAENT-UHFFFAOYSA-N 0.000 description 2
- OOOQNKMJLOLMHC-UHFFFAOYSA-N 5-[[3,4-diethyl-5-[[5-formyl-3-(3-hydroxypropyl)-4-methyl-1h-pyrrol-2-yl]methyl]-1h-pyrrol-2-yl]methyl]-4-(3-hydroxypropyl)-3-methyl-1h-pyrrole-2-carbaldehyde Chemical compound N1C(CC2=C(C(C)=C(C=O)N2)CCCO)=C(CC)C(CC)=C1CC=1NC(C=O)=C(C)C=1CCCO OOOQNKMJLOLMHC-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- RUDJVXPSZJOWCE-SZLYGITRSA-N CCCN(CCC)C(=O)CC(Br)C(=O)C1=C[Y]=CC=C1.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CCC(=O)C1=C[Y]=CC=C1.C[19F].C[19F].C[19F].C[19F].O=C(O)CCC(=O)C1=C[Y]=CC=C1 Chemical compound CCCN(CCC)C(=O)CC(Br)C(=O)C1=C[Y]=CC=C1.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CCC(=O)C1=C[Y]=CC=C1.C[19F].C[19F].C[19F].C[19F].O=C(O)CCC(=O)C1=C[Y]=CC=C1 RUDJVXPSZJOWCE-SZLYGITRSA-N 0.000 description 2
- ZIUGIHKQNZCSFB-UHFFFAOYSA-N CCCN(CCC)C(=O)CCC(=O)C1=CC=C(F)C=C1 Chemical compound CCCN(CCC)C(=O)CCC(=O)C1=CC=C(F)C=C1 ZIUGIHKQNZCSFB-UHFFFAOYSA-N 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 229960002143 fluorescein Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000003657 middle cerebral artery Anatomy 0.000 description 2
- 210000001700 mitochondrial membrane Anatomy 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- SLJDUPUOYWPBAB-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]-n-(6-phenoxypyridin-3-yl)acetamide Chemical compound COC1=CC=CC=C1CN(C(C)=O)C(C=N1)=CC=C1OC1=CC=CC=C1 SLJDUPUOYWPBAB-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ATNMPCPGYQSWBN-REOHCLBHSA-N (3s)-3-amino-4-chloro-4-oxobutanoic acid Chemical compound ClC(=O)[C@@H](N)CC(O)=O ATNMPCPGYQSWBN-REOHCLBHSA-N 0.000 description 1
- PVPBBTJXIKFICP-UHFFFAOYSA-N (7-aminophenothiazin-3-ylidene)azanium;chloride Chemical compound [Cl-].C1=CC(=[NH2+])C=C2SC3=CC(N)=CC=C3N=C21 PVPBBTJXIKFICP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YFXIZOLPHFYYMF-MIGPCILRSA-N 2-[6-chloro-2-[4-(3-fluoranylpropoxy)phenyl]imidazo[1,2-a]pyridin-3-yl]-n,n-diethylacetamide Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N(CC)CC)=C1C1=CC=C(OCCC[18F])C=C1 YFXIZOLPHFYYMF-MIGPCILRSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- FUSMPJDBORRTEC-UHFFFAOYSA-N 3-bromo-4-(4-bromophenyl)-4-oxo-N,N-dipropylbutanamide Chemical compound BrC(CC(=O)N(CCC)CCC)C(=O)C1=CC=C(C=C1)Br FUSMPJDBORRTEC-UHFFFAOYSA-N 0.000 description 1
- ZODFRCZNTXLDDW-UHFFFAOYSA-N 4-(4-bromophenyl)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1=CC=C(Br)C=C1 ZODFRCZNTXLDDW-UHFFFAOYSA-N 0.000 description 1
- WUYWHIAAQYQKPP-UHFFFAOYSA-N 4-(4-fluorophenyl)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C1=CC=C(F)C=C1 WUYWHIAAQYQKPP-UHFFFAOYSA-N 0.000 description 1
- DDGMDTGNGDOUPX-UHFFFAOYSA-N 7-methyliminophenothiazin-3-amine;hydrochloride Chemical compound [Cl-].C1=C(N)C=C2SC3=CC(=[NH+]C)C=CC3=NC2=C1 DDGMDTGNGDOUPX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BUNGCZLFHHXKBX-UHFFFAOYSA-N 8-methoxypsoralen Natural products C1=CC(=O)OC2=C1C=C1CCOC1=C2OC BUNGCZLFHHXKBX-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- MEUWWEBHNLWKAV-UHFFFAOYSA-N BrC(C(C(=O)N)(CCC)CCC)C(=O)C1=CC=C(C=C1)Br Chemical compound BrC(C(C(=O)N)(CCC)CCC)C(=O)C1=CC=C(C=C1)Br MEUWWEBHNLWKAV-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CWQXIVMZUQDEOE-UEWSIGOPSA-N CB1OC(C)(C)C(C)(C)O1.CBr.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CB1OC(C)(C)C(C)(C)O1.CBr.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 CWQXIVMZUQDEOE-UEWSIGOPSA-N 0.000 description 1
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical class CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 1
- BQMKSKPIASSEPT-XTKZWJJBSA-N CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21 BQMKSKPIASSEPT-XTKZWJJBSA-N 0.000 description 1
- BSPVQNZLIXRFTI-APSMZDQUSA-N CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.C[18F] Chemical compound CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.C[18F] BSPVQNZLIXRFTI-APSMZDQUSA-N 0.000 description 1
- NOVVHBNUGYSKHS-PJWPVRTPSA-N CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.C[Sn](C)(C)C Chemical compound CC.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=C[Y]=CC=C2)N=C2C(Cl)=CC(Cl)=CN21.C[Sn](C)(C)C NOVVHBNUGYSKHS-PJWPVRTPSA-N 0.000 description 1
- MQFIFXLTHYVLIA-DOEACTEGSA-N CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([I+]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([I+]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21 MQFIFXLTHYVLIA-DOEACTEGSA-N 0.000 description 1
- NLSJVFTZVHMPRY-SOTLUQEISA-N CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([I+]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([Sn](C)(C)C)C=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([I+]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([Sn](C)(C)C)C=C2)N=C2C(Cl)=CC(Cl)=CN21 NLSJVFTZVHMPRY-SOTLUQEISA-N 0.000 description 1
- GXRUXUOVSLBJKL-UHFFFAOYSA-N CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([IH]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CC1=CC=C(S(=O)(=O)[O-])C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C([IH]C3=CC=C(C)C=C3)C=C2)N=C2C(Cl)=CC(Cl)=CN21 GXRUXUOVSLBJKL-UHFFFAOYSA-N 0.000 description 1
- AXDJDENQSGMANL-UHFFFAOYSA-N CCCN(CCC)C(=O)CC(Br)C(=O)C1=CC=C(Br)C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C(Br)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([Sn](C)(C)C)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CCC(=O)C1=CC=C(Br)C=C1.O=C(O)CCC(=O)C1=CC=C(Br)C=C1 Chemical compound CCCN(CCC)C(=O)CC(Br)C(=O)C1=CC=C(Br)C=C1.CCCN(CCC)C(=O)CC1=C(C2=CC=C(Br)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([Sn](C)(C)C)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CCC(=O)C1=CC=C(Br)C=C1.O=C(O)CCC(=O)C1=CC=C(Br)C=C1 AXDJDENQSGMANL-UHFFFAOYSA-N 0.000 description 1
- KIUDJXCCMVZWQJ-UHFFFAOYSA-N CCCN(CCC)C(=O)CC1=C(C2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C(Br)C=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CCCN(CCC)C(=O)CC1=C(C2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C(Br)C=C2)N=C2C(Cl)=CC(Cl)=CN21 KIUDJXCCMVZWQJ-UHFFFAOYSA-N 0.000 description 1
- VBLCQMMYNMVPMP-DOEACTEGSA-N CCCN(CCC)C(=O)CC1=C(C2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21 Chemical compound CCCN(CCC)C(=O)CC1=C(C2=CC=C(B3OC(C)(C)C(C)(C)O3)C=C2)N=C2C(Cl)=CC(Cl)=CN21.CCCN(CCC)C(=O)CC1=C(C2=CC=C([18F])C=C2)N=C2C(Cl)=CC(Cl)=CN21 VBLCQMMYNMVPMP-DOEACTEGSA-N 0.000 description 1
- VEOBFBIRJULPRU-UHFFFAOYSA-N CCCN(CCC)C(=O)CCC(=O)C1=CC=C(Br)C=C1 Chemical compound CCCN(CCC)C(=O)CCC(=O)C1=CC=C(Br)C=C1 VEOBFBIRJULPRU-UHFFFAOYSA-N 0.000 description 1
- UHOQKWVTVRSJTL-UHFFFAOYSA-N CCCN(CCC)C(Cc1c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc(c(Cl)c2)[n]1cc2Cl)=O Chemical compound CCCN(CCC)C(Cc1c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc(c(Cl)c2)[n]1cc2Cl)=O UHOQKWVTVRSJTL-UHFFFAOYSA-N 0.000 description 1
- GNBASSDLAYGIBA-UHFFFAOYSA-N CCCNCC(C)C1=C(C(C=C2)=CC=C2[Sn](C)(C)C)N=C(C(Cl)=C2)N1C=C2Cl Chemical compound CCCNCC(C)C1=C(C(C=C2)=CC=C2[Sn](C)(C)C)N=C(C(Cl)=C2)N1C=C2Cl GNBASSDLAYGIBA-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- KGHNSNSWRMJVND-UHFFFAOYSA-N Hypocrellin Natural products COC1=CC(=O)C2=C3C4C(C(C(=O)C)C(C)(O)Cc5c(OC)c(O)c6C(=O)C=C(OC)C(=C13)c6c45)C(=C2O)OC KGHNSNSWRMJVND-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- RAVIZVQZGXBOQO-UHFFFAOYSA-N PK-11195 Chemical compound N=1C(C(=O)N(C)C(C)CC)=CC2=CC=CC=C2C=1C1=CC=CC=C1Cl RAVIZVQZGXBOQO-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- WBWBARLSYNQYAC-UHFFFAOYSA-N [4-[6,8-dichloro-3-[2-(dipropylamino)-2-oxoethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]-(4-methylphenyl)iodanium Chemical compound ClC=1C=C(C=2N(C=1)C(=C(N=2)C1=CC=C(C=C1)[I+]C1=CC=C(C=C1)C)CC(=O)N(CCC)CCC)Cl WBWBARLSYNQYAC-UHFFFAOYSA-N 0.000 description 1
- DPKHZNPWBDQZCN-UHFFFAOYSA-N acridine orange free base Chemical compound C1=CC(N(C)C)=CC2=NC3=CC(N(C)C)=CC=C3C=C21 DPKHZNPWBDQZCN-UHFFFAOYSA-N 0.000 description 1
- BGLGAKMTYHWWKW-UHFFFAOYSA-N acridine yellow Chemical compound [H+].[Cl-].CC1=C(N)C=C2N=C(C=C(C(C)=C3)N)C3=CC2=C1 BGLGAKMTYHWWKW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- BHPNXACHQYJJJS-UHFFFAOYSA-N bacteriochlorin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)CC2)=CC=C1C=C1CCC4=N1 BHPNXACHQYJJJS-UHFFFAOYSA-N 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical class C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DCRZYADKQRHHSF-UHFFFAOYSA-N daa-1106 Chemical compound COC1=CC=C(OC)C(CN(C(C)=O)C=2C(=CC=C(F)C=2)OC=2C=CC=CC=2)=C1 DCRZYADKQRHHSF-UHFFFAOYSA-N 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000005520 diaryliodonium group Chemical group 0.000 description 1
- 229940015493 dihematoporphyrin ether Drugs 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- ISVXIZFUEUVXPG-UHFFFAOYSA-N etiopurpurin Chemical compound CC1C2(CC)C(C(=O)OCC)=CC(C3=NC(C(=C3C)CC)=C3)=C2N=C1C=C(N1)C(CC)=C(C)C1=CC1=C(CC)C(C)=C3N1 ISVXIZFUEUVXPG-UHFFFAOYSA-N 0.000 description 1
- 239000004060 excitotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940020947 fluorescein sodium Drugs 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- BTXNYTINYBABQR-UHFFFAOYSA-N hypericin Chemical compound C12=C(O)C=C(O)C(C(C=3C(O)=CC(C)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 BTXNYTINYBABQR-UHFFFAOYSA-N 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- VANSZAOQCMTTPB-SETSBSEESA-N hypocrellin Chemical compound C1[C@@](C)(O)[C@@H](C(C)=O)C2=C(OC)C(O)=C3C(=O)C=C(OC)C4=C3C2=C2C3=C4C(OC)=CC(=O)C3=C(O)C(OC)=C21 VANSZAOQCMTTPB-SETSBSEESA-N 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960004469 methoxsalen Drugs 0.000 description 1
- SQBBOVROCFXYBN-UHFFFAOYSA-N methoxypsoralen Natural products C1=C2OC(=O)C(OC)=CC2=CC2=C1OC=C2 SQBBOVROCFXYBN-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- WIQKYZYFTAEWBF-UHFFFAOYSA-L motexafin lutetium hydrate Chemical compound O.[Lu+3].CC([O-])=O.CC([O-])=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 WIQKYZYFTAEWBF-UHFFFAOYSA-L 0.000 description 1
- SHXOKQKTZJXHHR-UHFFFAOYSA-N n,n-diethyl-5-iminobenzo[a]phenoxazin-9-amine;hydrochloride Chemical compound [Cl-].C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=[NH2+])C2=C1 SHXOKQKTZJXHHR-UHFFFAOYSA-N 0.000 description 1
- RAVIZVQZGXBOQO-CQSZACIVSA-N n-[(2r)-butan-2-yl]-1-(2-chlorophenyl)-n-methylisoquinoline-3-carboxamide Chemical compound N=1C(C(=O)N(C)[C@H](C)CC)=CC2=CC=CC=C2C=1C1=CC=CC=C1Cl RAVIZVQZGXBOQO-CQSZACIVSA-N 0.000 description 1
- LKKPNUDVOYAOBB-UHFFFAOYSA-N naphthalocyanine Chemical compound N1C(N=C2C3=CC4=CC=CC=C4C=C3C(N=C3C4=CC5=CC=CC=C5C=C4C(=N4)N3)=N2)=C(C=C2C(C=CC=C2)=C2)C2=C1N=C1C2=CC3=CC=CC=C3C=C2C4=N1 LKKPNUDVOYAOBB-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- MYFATKRONKHHQL-UHFFFAOYSA-N rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C2C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C21 MYFATKRONKHHQL-UHFFFAOYSA-N 0.000 description 1
- 229930187593 rose bengal Natural products 0.000 description 1
- 229940081623 rose bengal Drugs 0.000 description 1
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 1
- VDNLFJGJEQUWRB-UHFFFAOYSA-N rose bengal free acid Chemical compound OC(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C(O)=C(I)C=C21 VDNLFJGJEQUWRB-UHFFFAOYSA-N 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- BQJKVFXDDMQLBE-UHFFFAOYSA-N shiraiachrome A Natural products COC1=C2C3=C(OC)C=C(O)C4=C3C3=C5C(CC(C)(O)C(C(C)=O)C3=C(OC)C4=O)=C(OC)C(=O)C(C(O)=C1)=C25 BQJKVFXDDMQLBE-UHFFFAOYSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
Definitions
- the present invention relates to a fluorine-18-labeled positron emission tomography radiotracer for targeting translocator protein overexpression, a fluorescent ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor, and more particularly to: a fluorine-18-labeled positron emission tomography (PET) radiotracer which is produced using an iodonium salt or boron ester precursor and has an excellent ability to be selectively and specifically taken up into inflammatory regions in neuroinflammation and tumor models; a translocator protein overexpression-targeting fluorescent ligand for fluorescence imaging-guided surgery and photodynamic therapy, which is produced by introducing a fluorescent material instead of fluorine-18; and production methods therefor.
- PET positron emission tomography
- Microglial cells of the central nervous system contribute to the activation and homeostatic maintenance of the nervous system, and function to maintain neurons or cause apoptosis by secreting neurotrophins, nitric oxide, proinflammatory cytokines, or the like.
- the activation of microglial cells has been reported in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and diseases such as stroke, brain injury, and brain infection. It is also known that the deposition of beta amyloid, which is a factor associated with the onset and progression of Alzheimer's disease, causes the activation of microglial cells.
- TSPO 18-kDa translocator protein
- [ 11 C]DAA1106 has also been reported to have the problem of showing low TSPO-specific signals in TSPO.
- C-11-labeled AT-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine [ 11 C] PBR28) developed to overcome the pharmacokinetic disadvantages of this [ 11 C]DAA1106) has a high signal-to-noise ratio while maintaining the basic chemical structure of [ 11 C]DAA1106, and thus has been verified as an imaging radiotracer for translocator protein overexpression and researched clinically.
- [11C] PBR28 is also a compound labeled with carbon-11 having a short half-life, it is a radiotracer that can be used only for a short time after production, and has disadvantages in that it involves a high possibility of radiation exposure and can be applied only to a maximum of two patients depending on the number of PET systems after produced once.
- the aliphatic ethyl fluorine-18 used in the synthesis of [ 18 F]CB251 has an advantage in that the labeling method is simple, but has disadvantages in that it can be easily metabolized in vivo and in that when fluorine-18 ions produced by the metabolism, which are mainly taken up into bone, are taken up into bone, an image having a lower signal-to-noise ratio compared to a target site is provided.
- many research groups have attempted to develop compounds in which aromatic compounds are labeled directly with fluorine-18 to increase the in vivo stability of fluorine-18.
- This aromatic fluorine-18 labeling method is useful for providing in vivo images having a high signal-to-noise ratio by strong carbon-fluorine (C(sp2)-F) bonding, but the reactivity of the aromatic nucleophilic fluorine-18 label is lower than that of the aliphatic fluorine-18 label, and hence various precursors and reaction techniques for increasing the reactivity have still been developed. Accordingly, there is a need for a radiotracer capable of targeting overexpression of a disease-specific translocator protein while allowing simple and efficient labeling with the radioisotope fluorine-18 at the aromatic position of the target compound.
- ligands which have a high binding affinity for translocator protein and provide selective in vivo imaging, will expend their applications not only to radiotracers for PET imaging but also to fluorescent ligands for use in fluorescence imaging-guided surgery and photodynamic therapy which can visually provide information on tumor distribution by providing optimal images during surgery through the introduction of fluorescent materials.
- An object of the present invention is to provide: a PET imaging radiotracer for the diagnosis of neuroinflammation and cancer diseases associated with translocator protein overexpression, which is produced by labeling a translocator protein-targeting ligand with the positron-emitting nuclide fluorine-18; a fluorescent ligand for fluorescence imaging-guided surgery and photodynamic therapy, which is produced by introducing a fluorescent material instead of fluorine-18 to the same ligand; and production methods therefor.
- a method for producing a fluorine-18-labeled PET imaging radiotracer for targeting translocator protein overexpression including the steps of: preparing a fluorine-18 reaction solution by adding, to acetonitrile (CH 3 CN), water having dissolved therein fluorine-18 produced from a cyclotron, together with a phase transition catalyst, followed by heating to a temperature of 85 to 95° C.; producing either an iodonium salt precursor (type A precursor) by reacting 2-(4-trimethyltinaryl-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)dipropylacetamide with a (diacetoxy)iodoarene derivative, or a boron ester precursor (type B precursor) by reacting 2-(4-bromoaryl-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)dipropylacetamide with bis(pin
- the method may further include the first purification step of purifying the radiotracer composition by adding an aqueous hydrochloric acid solution to the radiotracer composition, followed by adsorption onto a C18 Sep-Pak cartridge, washing with water, and then elution with ethanol.
- the method may further include the second purification step of purifying the radiotracer composition using a high-performance liquid chromatography (HPLC) system equipped with a 244 to 264 nm UV detector and a radioisotope gamma-ray detector.
- HPLC high-performance liquid chromatography
- the step of producing the fluorine-18 reaction solution may be performed by further adding 18-crown-6 ([C 2 H 4 O] 6 )/cesium hydrogen carbonate (CsHCO 3 ) as the phase transition catalyst to increase the fluorine-18 labeling reactivity.
- 18-crown-6 [C 2 H 4 O] 6
- cesium hydrogen carbonate CsHCO 3
- a ligand and a fluorine-18-labeled PET imaging radiotracer for targeting translocator protein overexpression which are represented by Formula 1 below and produced either by a method including the steps of: preparing a solvent-evaporated fluorine-18 reaction solution by adding, to CH 3 CN, water having fluorine-18 dissolved therein, followed by heating to a temperature of 85 to 95° C.; producing an iodonium salt precursor (type A precursor) by reacting 2-(4-trimethyltinaryl-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)dipropylacetamide with (diacetoxy)iodoarene; preparing an iodonium salt precursor reaction solution by dissolving the iodonium salt precursor and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in CH 3 CN, and producing a radiotracer composition containing a fluorine-18-lab
- TEMPO 2,2,6,6-te
- R is 18 F or 19 F
- X is C or N
- Y is C or N.
- the 2-fluoroaryl-6,8-dichloroimidazopyridine derivative may be synthesized from an iodonium salt or boron ester precursor (type A or B precursor) represented by Formula 2 below:
- Z in Formula 2 above may be a functional group selected from the group consisting of iodobenzene tosylate, iodotoluene tosylate, 2-iodo-1,3,5-trimethylbenzene tosylate, 4-iodoanisole tosylate, 3-iodoanisole tosylate, 2-iodothiophene tosylate, 3-iodothiophene tosylate, iodobenzene bromide, iodotoluene bromide, 2-iodo-1,3,5-trimethylbenzene bromide, 4-iodoanizole bromide, 3-iodoanisole bromide, 2-iodocyophene bromide, 3-iodothiophene bromide, iodobenzene iodide, iodotoluene iodide, 2-iodo-1,3,5-trimethylbenz
- a fluorescent ligand for targeting translocator protein overexpression represented by Formula 3 below, which is produced by introducing a fluorescent dye or a sensitizer, which has a functional group for complementary bonding, to a 2-aryl-6,8-dichloroimidazopyridine derivative precursor substituted with one or more polyethylene glycol (PEG) chains containing a functional group, which is generally (universally) used for bonding with a fluorescent molecule as shown in Formula 4 below:
- the linker that connects the PEG to the fluorescent dye or the sensitizer may be a compound selected from the group consisting of ether, amide, ester, urea, urethane, thiourea, and disulfide, and the PEG is substituted at any one of the 2-, 3- and 4-positions of the ring containing X and Y.
- the fluorescent ligand having the fluorescent dye or sensitizer introduced thereto may be synthesized from a 2-aryl-6,8-dichloroimidazo[1,2-a]pyridine-3-yl)dipropylacetamide precursor substituted with one more polyethylene glycol (PEG) chains containing a terminal functional group capable of binding with a fluorescent molecule as shown in Formula 4 below:
- X is C or N
- Y is C or N
- the number (n) of the polyethylene glycol chains is 1 to 10.
- Z in Formula 4 may be a functional group selected from the group consisting of acid, alcohol, thiol, amine, isocyanate, isothiocyanate, bromide, iodide, chloride, N-succinimidyl ester, and sulfo-N-succinimidyl ester, and the PEG is substituted at any one of the 2-, 3- and 4-positions of the ring containing X and Y.
- FIG. 1 depicts a reaction scheme showing a process of synthesizing a fluorine-18-labeled radiotracer using an iodonium salt or boron ester precursor according to one embodiment of the present invention
- FIG. 2 depicts HPLC chromatograms showing the results of separating a pure fluorine-18-labeled radiotracer from a synthetic mixture, which is a derivative of Formula 2, in an example of the present invention
- FIG. 3 depicts HPLC chromatograms showing the results of injecting a pure fluorine-18-labeled radiotracer, which is a derivative of Formula 2, simultaneously with a reference material having a non-radioisotope, in order to check whether the pure fluorine-18-labeled radiotracer is the same as the reference material, in an example of the present invention
- FIG. 4 depicts images showing the uptake of the fluorine-18-labeleld radiotracer [ 18 F]BS224 ([ 18 F]BS compound, 18 F-labeled Bari and Seoul National University compound) in a portion having neuroinflammation induced by lipopolysaccharide (LPS) injected directly into the rat's brain in order to evaluate usefulness against neuroinflammation in a method for evaluating the biological results obtained using a fluorine-18-labeled radiotracer for PET imaging for targeting translocator protein overexpression, synthesized according to the present invention;
- LPS lipopolysaccharide
- FIG. 5 depicts images showing the uptake of a fluorine-18-labeleld radiotracer in a portion having cerebral ischemia induced in a middle cerebral artery occlusion ((MCA( ) rat model in order to evaluate diagnostic usefulness for stroke and cerebral infarction diseases in a method for evaluating the biological results obtained using the fluorine-18-labeled radiotracer [ 18 F]BS224 for PET imaging for targeting translocator protein overexpression, synthesized according to the present invention;
- MCA( ) rat model middle cerebral artery occlusion
- FIG. 6 is a table comparing the binding affinity of BS224 (Bari and Seoul National University compound 224), which is a ligand for targeting translocator protein overexpression according to the present invention, for TSPO or CBR, with the binding affinities of existing compounds known to bind to TSPO or CBR, in rat cerebrocortical samples;
- FIG. 7 compares the PET images acquired using the PET imaging radiotracer [ 18 F]BS224 for targeting translocator protein overexpression according to the present invention with the PET images acquired using existing [ 18 F]CB251 in normal persons;
- FIG. 8 compares TSPO PET images acquired from a normal person and a midbrain stroke patient using the ligand [ 18 F]BS224 for targeting translocator protein overexpression according to the present invention, and shows a graph comparing the radio activity in the lesion region with that of the normal person.
- FIG. 1 depicts a reaction scheme showing a process of synthesizing a fluorine-18-labeled radiotracer using an iodonium salt or boron ester precursor according to one embodiment of the present invention.
- FIG. 2 depicts HPLC chromatograms showing the results of separating a pure fluorine-18-labeled radiotracer from a synthetic mixture, which is a derivative of Formula 2, in an example of the present invention.
- FIG. 3 depicts HPLC chromatograms showing the results of injecting a pure fluorine-18-labeled radiotracer, which is a derivative of Formula 2, simultaneously with a reference material having a non-radioisotope, in order to check whether the pure fluorine-18-labeled radiotracer is the same as the reference material, in an example of the present invention.
- FIG. 4 depicts images showing the uptake of the fluorine-18-labeleld radiotracer [ 18 F]BS224 ([ 18 F]BS compound, 18 F-labeled Bari and
- LPS lipopolysaccharide
- FIG. 5 depicts images showing the uptake of a fluorine-18-labeleld radiotracer in a portion having cerebral ischemia induced in a middle cerebral artery occlusion ((MCA( ) rat model in order to evaluate diagnostic usefulness for stroke and cerebral infarction diseases in a method for evaluating the biological results obtained using the fluorine-18-labeled radiotracer [ 18 F]BS224 for PET imaging for targeting translocator protein overexpression, synthesized according to the present invention.
- MCA( ) rat model middle cerebral artery occlusion
- FIG. 6 is a table comparing the binding affinity of BS224 (Bari and Seoul National University compound 224), which is a ligand for targeting translocator protein overexpression according to the present invention, for TSPO or CBR, with the binding affinities of existing compounds known to bind to TSPO or CBR, in rat cerebrocortical samples.
- BS224 Bari and Seoul National University compound 224
- FIG. 7 compares the PET images acquired using the PET imaging radiotracer [ 18 F]BS224 for targeting translocator protein overexpression according to the present invention with the PET images acquired using existing [ 18 F]CB251 in normal persons.
- FIG. 8 shows TSPO PET images acquired from a normal person and a midbrain stroke patient using the ligand [ 18 F]BS224 for targeting translocator protein overexpression according to the present invention, brain PET images acquired from the same midbrain stroke patient, and a graph comparing the radio activity between the normal brain cell region and the lesion region in the PET images.
- a method for producing a fluorine-18-labeled PET imaging radiotracer for targeting translocator protein overexpression may include the steps of:
- an iodonium salt precursor (type A precursor) by reacting 2-(4-trimethyltinaryl-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)dipropylacetamide with a (diacetoxy)iodoarene derivative, or a boron ester precursor (type B precursor) by reacting 2-(4-bromoaryl-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)dipropylacetamide with bis(pinacolato)diboron;
- radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the iodonium salt precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction
- producing a radiotracer composition containing a fluorine-18-labeled radiotracer compound by adding the boron ester precursor reaction solution to the fluorine-18 reaction solution, followed by heating and reaction.
- the ligand and the fluorine-18-labeled PET imaging radiotracer for targeting translocator protein overexpression may be compounds represented by Formula 1 below:
- R is 18 F or 19 F
- X is C or N
- Y is C or N.
- the 2-fluoroaryl-6,8-dichloroimidazopyridine derivative may be synthesized from an iodonium salt or boron ester precursor (type A or B precursor) represented by Formula 2 below:
- the fluorine-18-labeled radiotracer of Formula 1 may be produced by reacting the iodonium salt or boron ester precursor of Formula 2 with a [ 18 F] cesium fluoride compound formed through the phase transition catalyst (18-crown-6/cesium hydrogen carbonate) added to increase the fluorine-18 labeling reactivity, thereby labeling the aromatic ring with 18 F:
- the reaction product of Reaction Scheme 1 above may be an iodonium salt or boron ester precursor, and Z in Reaction Scheme 1 above may be a functional group selected from the group consisting of iodobenzene tosylate, iodotoluene tosylate, 2-iodo-1,3,5-trimethylbenzene tosylate, 4-iodoanisole tosylate, 3-iodoanisole tosylate, 2-iodothiophene tosylate, 3-iodothiophene tosylate, iodobenzene bromide, iodotoluene bromide, 2-iodo-1,3,5-trimethylbenzene bromide, 4-iodoanizole bromide, 3-iodoanisole bromide, 2-iodocyophene bromide, 3-iodothiophene bromide, iodobenzene iodide,
- Y may be carbon in the case where X is nitrogen, and X may be carbon in the case where Y is nitrogen. Alternatively, both X and Y may be carbon.
- the introduction of 18 F may be performed by a process including the steps of: preparing a water-evaporated fluorine-18 reaction solution by heating to a temperature of 85 to 95° C.
- the compound of Formula 2 which is used as a starting material in the production of the fluorine-18-labeled radiotracer, has a structure in which the benzene or pyridine ring on the right side of the iodonium salt precursor is substituted with iodobenzene tosylate, iodotoluene tosylate, or the like, which results in the difference in electron density of the benzene or pyridine ring of the iodonium salt precursor between the two aromatics on both sides with respect to iodine.
- the substituent exhibits the effect of increasing the yield and selectivity while allowing the right ring of the iodonium salt precursor to be substituted directly with fluorine-18.
- the 2-fluoroaryl-6,8-dichloroimidazopyridine derivative represented by Formula 1 may be produced by the method shown in Reaction Scheme 2 below:
- compound d in Reaction Scheme 2 is a kind of 2-fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1.
- the fluoroaryl-6,8-dichloroimidazopyridine derivative may be produced through the steps of: producing compound (b) by reacting compound (a) with dipropylamine in the presence of 1,1′-carbonyldiimidazole and TEA in a tetrahydrofuran solvent (derivative production step 1); producing compound (c) by reacting compound (b) with bromine in a tetrachlorocarbon solvent (derivative production step 2); and producing compound (d) by reacting compound (c) with 2-amino-3,5-dichloropyridine in a dimethylformamide solvent (derivative production step 3).
- the intermediate product obtained in each step may be separated/purified by a filtration method, a purification method or the like known in the organic synthesis field.
- the fluorine-18 [ 18 E]-introduced fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1 may be produced from the iodonium salt or boron ester precursor represented by Formula 2 below:
- the iodonium salt or boron ester precursor of Formula 2 may be used as a starting material for producing the fluorine-18 [ 18 F]-introduced fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1.
- Z in Formula 2 allows the electron density of the right ring of the iodonium salt precursor to be different from that of the aromatic compound on the opposite side with respect to iodine, so that it exhibits the effect of increasing the yield and selectivity while allowing fluorine-18 to be introduced directly to the benzene or pyridine on the right side of the iodonium salt precursor.
- the produce of introducing a fluorine-containing -Z group to the 2-aryl-6,8-dichloroimidazopyridine derivative may be performed by the step of introducing the -Z group to the right ring of the 2-aryl-6,8-dichloroimidazopyridine derivative (compound (e)), as shown in Reaction Schemes 3 and 4 below:
- the compounds that are reacted with compound (3) to introduce the -Z group may be (diacetoxy)arene and para-toluene sulfonic acid.
- the compounds that are reacted with compound (g) to introduce a boron ester group may be bis(pinacolato)diboron and [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloride.
- the reaction of Reaction Scheme 3 may be performed by dissolving diacetoxyarene in a CH 3 CN solvent, adding para-toluene sulfonic acid thereto, and adding thereto dropwise a solution of a composition for the introduction of the -Z group in a chloroform solvent, followed by stirring at 50° C. for 15 to 18 hours.
- the reaction of Reaction Scheme 4 may be performed by adding, to a dimethylformamide solvent, a compound for the introduction of the -R group, bis(pinacolato)diboron and [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloride, followed by stirring at 80° C. for 5 hours.
- the present invention also provides a sensitizer-labeled, translocator protein overexpression-targeting tracer for fluorescence imaging-guided surgery and photodynamic therapy, which is represented by Formula 3 below and produced by a method including the step of producing a fluorescent ligand through a reaction between a 2-aryl-6,8-dichloroimidazopyridine derivative precursor substituted with one or more PEG chains having a functional group, which is generally (universally) used for bonding to a biomolecule as shown in Formula 4 below, and a fluorescent dye or photodynamic therapy sensitizer having a functional group for complementary bonding to the precursor:
- the linker that connects the PEG to the fluorescent dye or photodynamic therapy sensitizer may be a compound selected from the group consisting of ether, amide, ester, urea, urethane, thiourea, and disulfide, and the PEG is substituted at any one of the 2-, 3- and 4-positions of the ring containing X and Y.
- the PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative having a fluorescent dye or the sensitizer introduced thereto may be synthesized from a PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative precursor represented by Formula 4 below:
- X is C or N
- Y is C or N
- the number (n) of the polyethylene glycol chains is 1 to 10.
- Z in Formula 4 may be a functional group selected from the group consisting of acid, alcohol, thiol, amine, isocyanate, isothiocyanate, bromide, iodide, chloride, N-succinimidyl ester, and sulfo-N-succinimidyl ester, and the PEG is substituted at any one of the 2-, 3- and 4-positions of the ring containing X and Y.
- the PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative having a fluorescent dye or sensitizer introduced thereto as shown in Formula 3 above may be produced through a reaction between the 2-aryl-6,8-dichloroimidazopyridine derivative precursor, substituted with one or more PEG chains as represented by Formula 4 above, which have a functional group which is generally (universally) used to connect a particular molecule to a biomolecule by covalent bonding, and a fluorescent dye or photodynamic therapy sensitizer having a functional group for complementary bonding to the precursor.
- the fluorescent dye or sensitizer that is used in the present invention may be a compound selected from the group consisting of porphyrin-based compounds, porphyrin precursor-based compounds, phthalocyanine-based compounds, porphycene-based compounds, chlorine-based compounds, fluorescein-based compounds, anthracene-based compounds, hypericin, furocoumarin-based compounds, chlorophyll derivatives, purpurin-based compounds, phenothiazines, methylene blue, violet green, azure C, thionine, nile blue A, hypocrellin, rose bengal, rhodamine 123, IR-700, IR-780, PC-413, and lutetium texaphyrin.
- the porphyrin-based compound may be selected from the group consisting of hematoporphyrin derivatives, dihematoporphyrin ether/ester, porfimer sodium, tetrasodium-meso-tetraphenylporphyrin-sulphonate, and metallotetra-azaporphyrin.
- the porphyrin precursor-based compound may be selected from the group consisting of d-aminolevulinic acid (ALA), d-aminolevulinic acid (ALA)-methyl-, propyl-, and hexyl-esters.
- ALA d-aminolevulinic acid
- ALA d-aminolevulinic acid
- the phthalocyanine-based compound may be selected from the group consisting of chloroaluminum tetra-sulfonated phthalocyanine, zinc(II) phthalocyanine, silicone naphthalocyanine, and aluminum sulfonated phthalocyanine.
- the porphycene-based compound may be selected from the group consisting of 9-acetoxy-2,7,12,17-tetra-N-propylporphycene, 2-hydroxyethyl-7,12,17-tris(methoxyethyl)porphycene, and 23-carboxy-24-methoxycarbonylbenzo(2,3)-7,12,17-tri(methoxyethyl)-porphycene.
- the chlorine-based compound may be selected from the group consisting of mono-aspartyl chlorine e6, diaspartyl chlorine e6, chlorine e6 sodium, and bacteriochlorin.
- the fluorescein-based compound may be selected from the group consisting of fluorescein sodium and tetrabromofluorescein-eosin.
- the anthracene-based compound may be selected from the group consisting of anthraquinone, acridine orange, and acridine yellow.
- the furocoumarin-based compound may be selected from the group consisting of 5-methooxypsoralen and 8-methoxypsoralen.
- the purpurin-based compound may be selected from the group consisting of metallopurpurin and tin etiopurpurin.
- the fluorine-18-introduced 2-fluoroaryl-6,8-dichloroimidazopyridine derivative of Formula 1 has a high binding affinity for TSPO present in the outer mitochondrial membrane in cells, and thus may be a PET radiotracer for diseases related to TSPO overexpression.
- the positrons released from fluorine-18 after binding to TSPO in the body meet electrons in the body and annihilate.
- Two gamma-ray energies (511 keV) produced during the annihilation may be collected and a relevant region showing high specific expression of TSPO in the body may be directly and non-invasively imaged by PET.
- the fluorescent molecule-introduced 2-aryl-6,8-dichloroimidazopyridine derivative of Formula 3 may bind to cancer cells specifically expressing TSPO in the body by a mechanism similar to the above-described mechanism, thus providing an image guide to a correct tumor site during tumor surgery.
- it may be used as a sensitizer that can more effectively receive the light in the therapeutic wavelength range from an affected area.
- it may be used in photodynamic therapy in which it binds directly to TSPO in a tumor, and then induces cell necrosis when locally exposed to a light source.
- the 2-aryl-6,8-dichloroimidazopyridine derivative compound having the property of binding to TSPO overexpressed in vivo and is injected in vivo and the relevant region is irradiated with light having a specific wavelength corresponding to the fluorescent dye after sufficient targeting of TSPO the substance bound thereto can be visualized by light emission, thus providing guidelines for tumor surgery.
- the 2-aryl-6,8-dichloroimidazopyridine derivative having introduced thereto a sensitizer for photodynamic therapy can treat a tumor by releasing reactive oxygen species into the relevant region when receiving light having a specific wavelength.
- the uptake and release of the 2-aryl-6,8-dichloroimidazopyridine derivative in a brain and a tumor may be controlled by modifying X or Y of the aryl on the right side of the 2-aryl-6,8-dichloroimidazopyridine derivative of Formula 1 or 2 or by changing the position of substitution of fluorine-18 or a fluorescent dye or sensitizer introduced via one or more PET chains. If necessary, the uptake and release rates of the derivative may be controlled by increasing the polarity of these substituents.
- the 2-aryl-6,8-dichloroimidazopyridine derivatives of Formulas 1 and 3 according to the present invention may advantageously be used to determine whether various brain diseases and tumors associated with translocator protein overexpression are present or to diagnose and treat the relevant region by administration to mammals, preferably humans.
- Step 2 Preparation of 3-bromo-4-(4-bromophenyl)-4-oxo-dipropylbutanamide
- Step 3 Preparation of 2-(2-(4-bromophenyl)-6,8-dichloro-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide
- Step 4 Preparation of 2-(6,8-dichloro-2-(4-(trimethylstannyl)phenyl)-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide
- a product having high molar activity can be obtained.
- a fluorine-18 reaction solution is prepared by adding, to CH 3 CN, water containing fluorine-18 dissolved therein.
- diaryliodonium salt whose aromatic ring compound can be labeled with nucleophilic fluorine-18 without having to use a separate electron-attracting functional group
- 2-(6,8-dichloro-2-(4-(trimethylstannyl)phenyl)-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide is produced and reacted with 4-(diacetoxy)iodoarene to obtain a ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor.
- This iodonium salt precursor is dissolved in CH 3 CN to obtain an iodonium salt reaction solution.
- a radiotracer composition [ 18 F]BS224) containing a fluorine-18-labeled radiotracer compound may be easily obtained.
- the step of producing the ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor by reacting 2-(6,8-dichloro-2-(4-(trimethylstannyl)phenyl)-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide with 4-(diacetoxy)iodotoluene may be performed, as shown in Reaction Scheme 5 below.
- the step of preparing the fluorine-18 reaction solution may be performed by further adding cesium hydrogen carbonate/18-crown-6 to CH 3 CN to promote the reactivity of fluorine.
- the production method may further include the first purification step of purifying the radiotracer composition by adding an aqueous hydrochloric acid solution to the radiotracer composition, followed by adsorption onto a C18 Sep-Pak cartridge, washing with water, and then elution with ethanol.
- the production method may further include the second purification step of purifying the radiotracer composition using a high-performance liquid chromatography (HPLC) system equipped with a 244 to 264 nm UV detector and a radioisotope gamma-ray detector.
- HPLC high-performance liquid chromatography
- a PEG chain-substituted 2-aryl-6,8-dichloroimidazopyridine derivative having a sensitizer introduced thereto as shown in Formula 3 above may be produced by introducing, for example, an IR-780 compound, through amide bonding, as shown in Reaction Scheme 6 below:
- This compound produced by introducing the photosensitizer IR-780 compound to the 2-aryl-6,8-dichloroimidazopyridine derivative has the following advantages when used in photodynamic therapy. Since IR-780 acts as a compound that generates heat in cells, into which it has been taken up, when receiving light having a specific wavelength (780 to 800 nm), a therapy that burns a tumor by heat generated by irradiating light into a region into which the compound has been taken up may be applied even to a case in which surgery for selectively removing a tumor such as a bladder tumor is difficult and to a tumor therapy in which the functionality of an organ is highly likely to be lost due to surgery.
- the present invention also provides a fluorine-18-labeled PET radiotracer ([ 18 F]BS224) for targeting translocator protein overexpression represented by Formula 5 below, which is produced by a method including the steps of: preparing a water-evaporated fluorine-18 reaction solution by adding water containing fluorine-18 dissolved thereto to CH 3 CN, followed by heating to a temperature of 85 to 95° C.; producing a ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor as an iodonium salt precursor by reacting a 2-trimethyltinaryl-6, 8-dichloroimidazopyridine derivative with 4-(diacetoxy)iodoarene; preparing an iodonium salt precursor reaction solution by dissolving the precursor and 2,2,6,6-tetramethyl-1-
- the fluorine-18-labeled PET radiotracer ([ 18 F]BS224, 2-(6,8-dichloro-2-(4-[ 18 F]fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide) for targeting translocator protein overexpression according to the present invention makes it possible to obtain new images of neuroinflammation and tumors associated with translocator protein overexpression by positron emission tomography, thus diagnosing patients with various brain diseases and tumors associated with translocator protein overexpression.
- the PET radiotracer of the present invention can provide brain neuroinflammation and tumor imaging diagnostics to a larger number of patients compared to conventional carbon-11 tracers.
- a 2-pyridyl-6,8-dichloroimidazopyridine derivative may be synthesized as shown in Reaction Scheme 6 such that it has a pyridine ring instead of the benzene ring on the right side of the [ 18 F]BS224 compound.
- the release of the synthesized derivative compound in a normal brain is suppressed, and thus the synthesized derivative compound may more rapidly provide the difference between a TSPO-overexpressing region and normal cells.
- Example 1 Synthesis of 2-(6,8-dichloro-2-(4-[ 18 F] fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide using iodonium salt precursor
- iodonium salt precursor (4 mg, (4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (p-tolyl)iodonium) and 1 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy were dissolved in 0.3 ml of acetonitrile (container 2), and then the solution was added to container 1, followed by reaction by heating at 140° C. for 10 minutes.
- the eluted solution was purified using an HPLC system (Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min) equipped with a 254 nm UV detector and a radioisotope gamma-ray detector, and fluorine-18-labeled [ 18 F]BS224 was isolated with a radiochemical yield of about 25% at 34 minutes.
- HPLC system Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min
- a boron ester precursor (3 mg, 2-(6,8-dichloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imidazo[1,2-a]pyridin-3-yl-N,N-dipropylacetamide) and a copper catalyst (0.2 mg of copper(II) trifluoromethanesulfonate, or 0.4 mg of tetrakis(pyridine)copper(II) triflate) were dissolved in 0.5 ml of acetonitrile (container 2), and then the solution was added to container 1, followed by reaction by heating at 110° C. for 10 minutes.
- the eluted solution was purified using an HPLC system (Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min) equipped with a 254 nm UV detector and a radioisotope gamma-ray detector, and fluorine-18-labeled [ 18 F]BS224pyridine was isolated with a radiochemical yield of about 9% at 34 minutes.
- HPLC system Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min
- reaction mixture was purified using an HPLC system (Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min) equipped with a 254 nm UV detector and a radioisotope gamma-ray detector, and 2-(6,8-dichloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (BS224) was isolated at about 34 minutes.
- HPLC system Waters, Xterra Semi-preparative C18 column, 10 ⁇ 250 mm, 10 ⁇ m; 50% acetonitrile-water, 254 nm, flow rate: 5.0 mL/min
- reaction mixture was filtered through celite, and then extracted with water and dichloromethane.
- the extracted organic solvent was dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography to afford the desired compound.
- a neuroinflammatory rat model male Sprague-Dawley rats weighing 200 to 250 g were used. The rats were anesthetized, the skull was exposed, and a small hole was punctured using a bone drill. Next, 50 ⁇ g of LPS was infused into the predetermined right striatum by the use of a Hamilton syringe at a flow rate of 0.5 ⁇ L/min (AP, 0.8 mm; L, ⁇ 2.7 mm and P, ⁇ 5.0 mm from the bregma). The Hamilton syringe was sustained in place for 10 min to avoid the backflow of LPS. The small hole in the skull was filled with wax, and the incised scalp was sutured.
- AP 0.8 mm
- L ⁇ 2.7 mm
- P ⁇ 5.0 mm from the bregma
- a nylon probe was inserted through the incision to the middle cerebral artery. After inserting the probe, the incised neck portion was closed with a stapler, and then the blood flow was blocked for 60 minutes. After removing the stapler, the probe was carefully pulled out and the threads on both sides of the internal carotid artery were removed. Among the two threads, the thread in the direction of the middle cerebral artery was tied again, and then the thread in the total carotid artery was removed. The incised neck portion was sutured.
- [ 18 F]BS224 dispersed in 5% ethanol/saline was added to and mixed with n-octanol (5 mL) and sodium phosphate buffer (0.15 M, pH 7.4, 5.0 mL), and then lipophilicity was measured five times. Samples of each phase were counted for radioactivity, and the lipophilicity was expressed as the ratio of the counts per minute from n-octanol versus that of the sodium phosphate buffer. The lipophilicity of [ 18 F]BS224 was 2.78 ⁇ 0.4.
- the present invention provides a method for producing a fluorine-18-labeled PET radiotracer for targeting translocator protein overexpression, the method including the steps of: preparing a solvent-evaporated fluorine-18 reaction solution by adding water having fluorine-18 dissolved therein to CH 3 CN, followed by heating to a temperature of 85 to 95° C.; producing a ((4-(6,8-dichloro-3-(2-(dipropylamino)-2-oxoethyl)imidazo[1,2-a]pyridin-2-yl)phenyl) (aryl)iodonium) anion precursor as an iodonium salt precursor by reacting 2-(6,8-dichloro-2-(4-(trimethylstannyl)phenyl)-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide with 4-(diacetoxy)iodotoluene; producing 2-(6,8-dichloro-2
- the use of the fluorine-18-labeled PET radiotracer for targeting translocator protein radiotracer according to the present invention makes it possible to diagnose patients with various brain diseases and tumors by obtaining new images of neuroinflammation, stroke and tumors associated with translocator protein overexpression through PET.
- the PET radiotracer of the present invention can provide brain neuroinflammation and tumor imaging diagnostics to a larger number of patients compared to conventional carbon-11 tracers.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nuclear Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/419,562 US20240156997A1 (en) | 2018-01-19 | 2024-01-23 | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2018-0007226 | 2018-01-19 | ||
KR1020180007226A KR102031652B1 (ko) | 2018-01-19 | 2018-01-19 | 전이체 단백질 과발현 관련 질환의 양성자방출단층촬영 방사성추적자, 형광영상 진단 및 광역학 치료를 위한 전이체 단백질 표적 리간드 및 이의 제조방법 |
PCT/KR2018/015117 WO2019143016A1 (ko) | 2018-01-19 | 2018-11-30 | 전이체 단백질 과발현 관련 질환의 양성자방출단층촬영 방사성추적자, 형광영상 진단 및 광역학 치료를 위한 전이체 단백질 표적 리간드 및 이의 제조방법 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2018/015117 Continuation WO2019143016A1 (ko) | 2018-01-19 | 2018-11-30 | 전이체 단백질 과발현 관련 질환의 양성자방출단층촬영 방사성추적자, 형광영상 진단 및 광역학 치료를 위한 전이체 단백질 표적 리간드 및 이의 제조방법 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/419,562 Continuation US20240156997A1 (en) | 2018-01-19 | 2024-01-23 | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor |
Publications (1)
Publication Number | Publication Date |
---|---|
US20200345870A1 true US20200345870A1 (en) | 2020-11-05 |
Family
ID=67301462
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/929,803 Abandoned US20200345870A1 (en) | 2018-01-19 | 2020-07-15 | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor |
US18/419,562 Pending US20240156997A1 (en) | 2018-01-19 | 2024-01-23 | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US18/419,562 Pending US20240156997A1 (en) | 2018-01-19 | 2024-01-23 | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor |
Country Status (6)
Country | Link |
---|---|
US (2) | US20200345870A1 (ko) |
EP (1) | EP3741392A4 (ko) |
JP (1) | JP7320850B2 (ko) |
KR (1) | KR102031652B1 (ko) |
CN (1) | CN111954543A (ko) |
WO (1) | WO2019143016A1 (ko) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102150377B1 (ko) * | 2020-03-26 | 2020-09-01 | 서울대학교산학협력단 | 플루오린-18이 치환된 피라졸 유도체 방사성의약품 제조방법 |
KR20230126855A (ko) * | 2022-02-24 | 2023-08-31 | 서울대학교산학협력단 | 미토콘드리아 표적 암 치료용 조성물 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100549213B1 (ko) * | 2003-01-15 | 2006-02-03 | 학교법인 인하학원 | 플루오린-18로 표지된 유기플루오로화합물의 제조방법 |
GB0407952D0 (en) * | 2004-04-08 | 2004-05-12 | Amersham Plc | Fluoridation method |
PL2146944T3 (pl) * | 2007-04-11 | 2014-05-30 | Merck & Cie | Sposób otrzymywania folianów znakowanych fluorem-18 |
EP2190844B3 (en) | 2007-08-15 | 2013-07-17 | Arena Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
CA2710016A1 (en) | 2007-12-21 | 2009-07-02 | The University Of Sydney | Translocator protein ligands |
EP2085390A1 (en) * | 2008-01-31 | 2009-08-05 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Labelled analogues of halobenzamides as multimodal radiopharmaceuticals and their precursors |
JP2012500225A (ja) | 2008-08-19 | 2012-01-05 | ザ ユニバーシティ オブ シドニー | 新規な化合物および診断におけるその使用 |
WO2010053218A1 (en) * | 2008-11-06 | 2010-05-14 | Snu R&Db Foundation | Fluorinated benzothiazole derivatives, preparation method thereof and imaging agent for diagnosing altzheimer's disease using the same |
JP2013521233A (ja) | 2010-02-25 | 2013-06-10 | ヤンセン アルツハイマー イミュノセラピー | Aβを標的とする免疫療法のPETモニタリング |
KR101441406B1 (ko) * | 2011-05-25 | 2014-11-04 | 주식회사 바이오이미징코리아 | 디아릴이오도늄 염 전구체를 이용한 플로오린-18이 표지된 플루마제닐의 제조 방법 |
GB201405002D0 (en) * | 2014-03-20 | 2014-05-07 | Isis Innovation | Fluorination method |
KR101605291B1 (ko) * | 2014-11-07 | 2016-03-21 | 재단법인 아산사회복지재단 | 유기 플루오르화 지방족 화합물의 제조방법 및 정제방법 |
-
2018
- 2018-01-19 KR KR1020180007226A patent/KR102031652B1/ko active IP Right Grant
- 2018-11-30 WO PCT/KR2018/015117 patent/WO2019143016A1/ko unknown
- 2018-11-30 CN CN201880087109.XA patent/CN111954543A/zh active Pending
- 2018-11-30 JP JP2020539800A patent/JP7320850B2/ja active Active
- 2018-11-30 EP EP18901257.8A patent/EP3741392A4/en active Pending
-
2020
- 2020-07-15 US US16/929,803 patent/US20200345870A1/en not_active Abandoned
-
2024
- 2024-01-23 US US18/419,562 patent/US20240156997A1/en active Pending
Non-Patent Citations (2)
Title |
---|
Mossine et al. Org. Lett. 2015, 17, 5780-5783. (Year: 2015) * |
Mossine et al. Org. Lett. 2015, 17, S1-S72. (Year: 2015) * |
Also Published As
Publication number | Publication date |
---|---|
KR102031652B1 (ko) | 2019-10-14 |
CN111954543A (zh) | 2020-11-17 |
EP3741392A1 (en) | 2020-11-25 |
EP3741392A4 (en) | 2022-01-12 |
WO2019143016A9 (ko) | 2020-08-20 |
US20240156997A1 (en) | 2024-05-16 |
WO2019143016A1 (ko) | 2019-07-25 |
JP2021511329A (ja) | 2021-05-06 |
KR20190088756A (ko) | 2019-07-29 |
JP7320850B2 (ja) | 2023-08-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20240156997A1 (en) | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging-guided surgery and photodynamic therapy, and production methods therefor | |
JP6216421B2 (ja) | 造影剤の合成および使用のための組成物、方法およびシステム | |
RU2468014C2 (ru) | Фторсодержащие лиганды для нацеливания периферических бензодиазепиновых рецепторов | |
JP2019055973A (ja) | Psma結合剤及びその使用 | |
Pichika et al. | Nicotinic α4β2 receptor imaging agents: part II. Synthesis and biological evaluation of 2-[18F] fluoro-3-[2-((S)-3-pyrrolinyl) methoxy] pyridine (18F-nifene) in rodents and imaging by PET in nonhuman primate | |
KR20090028714A (ko) | 전좌 단백질(18 KDA)의 리간드로서의 2-아릴피라졸로[L,5-α]피리미딘-3-일 아세트아미드 유도체 | |
WO2012161177A1 (ja) | 腫瘍の画像診断用標識誘導体 | |
BRPI0806621A2 (pt) | composto, uso de um composto, composição farmacêutica, e, método in vivo para medir depósitos amilóides em um indivìduo | |
KR20190030727A (ko) | Ido1 효소를 영상화하기 위한 방사성리간드 | |
AU2015326506B2 (en) | Novel anthranilic acid derivatives | |
US20090234162A1 (en) | Radioactive Halogen-Labeled Phenyloxyaniline Derivatives | |
KR101602912B1 (ko) | [18f]플루오르메틸기가 도입된 뇌신경염증 표적 양성자방출단층촬영 방사성추적자, 이의 합성 및 그를 이용한 생물학적 결과 평가 방법 | |
JP2012500225A (ja) | 新規な化合物および診断におけるその使用 | |
JP5196561B2 (ja) | 核医学診断用医薬 | |
EP2657213A1 (en) | Labelled quinoxaline derivatives as multimodal radiopharmaceuticals and their precursors | |
Qu et al. | Radioiodinated aza-diphenylacetylenes as potential SPECT imaging agents for β-amyloid plaque detection | |
KR101441406B1 (ko) | 디아릴이오도늄 염 전구체를 이용한 플로오린-18이 표지된 플루마제닐의 제조 방법 | |
JP6273251B2 (ja) | 芳香族アミノ酸誘導体およびそれを用いるpetプローブ | |
US20220372045A1 (en) | Deuterated compounds and imaging agents for imaging huntingtin protein | |
WO2023063154A1 (ja) | 放射性pet診断用トレーサー組成物、その中間体、その製造方法 | |
WO2014163106A1 (ja) | アセチルコリン小胞トランスポーターの検出に適した化合物 | |
JP2014218455A (ja) | スチリルピリジン誘導体化合物 | |
JP2014218454A (ja) | スチリルピリジン誘導体化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SEOUL NATIONAL UNIVERSITY R&DB FOUNDATION, KOREA, REPUBLIC OF Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KIM, SANG EUN;LEE, BYUNG CHUL;LEE, SANG HEE;AND OTHERS;SIGNING DATES FROM 20200708 TO 20200713;REEL/FRAME:053224/0603 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE AFTER FINAL ACTION FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: ADVISORY ACTION MAILED |